Genomic Activation of PPARG Reveals a Candidate Therapeutic Axis in Bladder Cancer

Total Page:16

File Type:pdf, Size:1020Kb

Genomic Activation of PPARG Reveals a Candidate Therapeutic Axis in Bladder Cancer Author Manuscript Published OnlineFirst on September 18, 2017; DOI: 10.1158/0008-5472.CAN-17-1701 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. RXRA and PPARG in Bladder Cancer Genomic activation of PPARG reveals a candidate therapeutic axis in bladder cancer Jonathan T. Goldstein1, Ashton C. Berger1, Juliann Shih1, Fujiko F. Duke1, Laura Furst1, David J. Kwiatkowski2, Andrew D. Cherniack1,3, Matthew Meyerson1,3,4,5 and Craig A. Strathdee1 Affiliations: 1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America. 2Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America, 3Department of Medical Oncology, Dana- Farber Cancer Institute, Boston, Massachusetts, United States of America, 4Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America. 5Department of Pathology, Harvard Medical School, Boston, Massachusetts, United States of America. Current address for F. Duke: Gritstone Oncology, Cambridge, MA USA. Running title: RXRA and PPARG in bladder cancer Keywords: RXRA, PPARG, Genitourinary cancers: bladder, Nuclear receptors: structure and function Additional information. Financial support: Financial support for this work was provided by Bayer AG (Berlin, Germany) (J.Goldstein, A.Berger, J.Shih, F.Duke, L.Furst, A.Cherniack, M.Meyerson, and C.Strathdee) and the National Cancer Institute under grant 5R35CA197568-02 (M. Meyerson). Corresponding Author: Matthew Meyerson, Dana-Farber Cancer Institute, Boston, MA, 02115, USA; Tel: 617-632-4768, Email: [email protected] Conflict of interest disclosure statement; The Broad Institute and Dana-Farber Cancer Institute have filed a patent application for aspects of the work described in this paper. Financial support for this work was provided by Bayer AG (Berlin, Germany). M. Meyerson is a member of the Scientific Advisory Board and equity holder of Origimed. 1 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 18, 2017; DOI: 10.1158/0008-5472.CAN-17-1701 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. RXRA and PPARG in Bladder Cancer Abstract The PPARG gene encoding the nuclear receptor PPAR-gamma is activated in bladder cancer, either directly by gene amplification or mutation, or indirectly by mutation of the RXRA gene which encodes the heterodimeric partner of PPAR-gamma. Here we show that activating alterations of PPARG or RXRA lead to a specific gene expression signature in bladder cancers. Reducing PPARG activity, whether by pharmacologic inhibition or genetic ablation, inhibited proliferation of PPARG-activated bladder cancer cells. Our results offer a preclinical proof of concept for PPARG as a candidate therapeutic target in bladder cancer. 2 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 18, 2017; DOI: 10.1158/0008-5472.CAN-17-1701 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. RXRA and PPARG in Bladder Cancer Introduction Bladder cancer is the fifth most commonly diagnosed cancer in the United States with an annual incidence of 80,000 cases and an annual mortality of 15,000. Most patients are diagnosed with non-invasive/superficial urothelial carcinoma of the bladder and respond well to transurethral resection, Bacillus Calmette-Guérin (BCG) immunotherapy, and regular cystoscopic surveillance, with a 5-year survival rate of 96%. Patients diagnosed with muscle-invasive disease have a poorer prognosis, however, with a 5-year survival rate of 35- 70%, depending upon the extent of invasion, regional and systemic metastases, and response to therapy. Recently several immune checkpoint blockade drugs have been FDA- approved for treatment of urothelial carcinoma, including atezolizumab, an anti- PD-L1 antibody, in 2016 (1); nivolumab and pembrolizumab, anti-PD-1 antibodies, in 2017 (2) ; and avelumab and durvalumab, anti-PD-L1 antibodies, in 2017 (3,4). These approvals mark the first new drugs for metastatic bladder cancer in over 20 years. However, the objective response rates (defined using RECIST v1.1) were relatively low in these clinical trials, with 15-20% overall response rate and 26-28% response rate in PD-L1-positive patients (1,2). Beyond checkpoint inhibitors, a number of therapies targeting specific genetic alterations, including FGFR3 alterations, mTOR pathway alterations, and DNA repair deficiencies associated with ERCC2 alterations (5-8), are under clinical 3 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 18, 2017; DOI: 10.1158/0008-5472.CAN-17-1701 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. RXRA and PPARG in Bladder Cancer evaluation. We explored large-scale cancer genome datasets derived from patients with muscle-invasive bladder cancer with the purpose of identifying novel therapeutic targets. Hotspot mutations (p.S427F/Y) in the retinoid X receptor alpha (RXRA) gene are present in ~5% of bladder cancer samples (9,10). RXRA is a well characterized ligand-activated nuclear receptor that serves as a requisite heterodimer partner for ~30 nuclear receptors, including PPARA, PPARG, PPARD, RARA, RARB, VDR, TR, LXR, and PXR (11), suggesting that recurrent mutations in RXRA could impact the formation and/or function of these heterodimers and change the expression of their downstream target genes. Previous reports have shown that cancer samples containing RXRA p.S427F/Y mutations are associated with enhanced expression of genes involved in adipogenesis and lipid metabolism, including ACOX1, ACSL1, ACSL5, FABP4, and HMGS2 (9). These genes are targets of peroxisome proliferator-activated receptor gamma (PPARG), a member of the PPAR subfamily of nuclear receptors. Interestingly, the PPARG gene is focally amplified in 15% of bladder cancer samples (Supplementary Fig. 1A and (12)). This amplification is strongly correlated with expression of PPARG (Supplementary Fig. 1B) as well as expression of PPARG target genes and luminal differentiation markers such as GATA3, UPK2, ACOX1, and UPK1A (Supplementary Fig. 1C and (13-16)). PPARG is a master regulator of adipocyte differentiation and controls 4 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 18, 2017; DOI: 10.1158/0008-5472.CAN-17-1701 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. RXRA and PPARG in Bladder Cancer expression of a large set of genes involved in lipid and glucose homeostasis (12). In contrast to PPARG’s well-characterized activity in adipocytes, however, little is known about its function in the urinary bladder and in the pathogenesis of bladder cancer. The potential risk of bladder cancer upon activation of the PPAR subfamily of nuclear receptors is controversial, and was first suggested following rodent toxicity studies testing anti-diabetic PPAR agonists in which numerous glitazar- class PPARA/PPARG dual agonist compounds were associated with an increased incidence of bladder cancer (17). In terms of more selective PPARG agonists, also anti-diabetic drugs with insulin sensitizing activity, the carcinogenic effect in rodents was also observed with pioglitazone, which has weak PPARA activity (18), but not with rosiglitazone, which is highly selective for PPARG (17,19). In a more sensitive, chemically-induced model using the carcinogen, 4-hydroxybutyl (butyl) nitrosamine (OH-BBN), rosiglitazone was found to potentiate urinary bladder carcinogenesis in rats compared to OH-BBN alone (20). It was originally hypothesized that the effects of PPARA/PPARG dual agonists on promoting bladder cancer was rodent-specific due to indirectly causing calcium crystal formation in the bladder resulting in urolithiasis (21). Numerous studies have since examined the incidence of bladder cancer in humans following the clinical use of these compounds, with some detecting an increased risk and others concluding there is no increased risk (22,23). The most comprehensive retrospective study to date showed an increase in the 5 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 18, 2017; DOI: 10.1158/0008-5472.CAN-17-1701 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. RXRA and PPARG in Bladder Cancer hazard ratio for bladder cancer with long-term, high-dose treatment with pioglitazone (24). Based on the combined genetic and pharmacologic evidence, we hypothesized that activation of PPARG is oncogenic in the transitional epithelial cells of the bladder. We evaluated this by investigating the biological impact of ectopic expression of mutant alleles of RXRA and PPARG, pharmacologic ablation of RXRA/PPARG signaling using small molecule perturbagens, and genetic ablation of RXRA and PPARG using CRISPR/Cas9 gene knockouts. Our results demonstrate an oncogenic role for PPARG in the
Recommended publications
  • Research Article Gene Knockout Identification Using an Extension of Bees Hill Flux Balance Analysis
    Hindawi Publishing Corporation BioMed Research International Volume 2015, Article ID 124537, 10 pages http://dx.doi.org/10.1155/2015/124537 Research Article Gene Knockout Identification Using an Extension of Bees Hill Flux Balance Analysis Yee Wen Choon,1 Mohd Saberi Mohamad,1 Safaai Deris,1 Chuii Khim Chong,1 Sigeru Omatu,2 and Juan Manuel Corchado3 1 Artificial Intelligence and Bioinformatics Research Group, Faculty of Computing, Universiti Teknologi Malaysia, 81310 Skudai, Johor, Malaysia 2 Department of Electronics, Information and Communication Engineering, Osaka Institute of Technology, Osaka 535-8585, Japan 3 Biomedical Research Institute of Salamanca/BISITE Research Group, University of Salamanca, 37008 Salamanca, Spain Correspondence should be addressed to Mohd Saberi Mohamad; [email protected] Received 21 August 2014; Revised 22 October 2014; Accepted 31 October 2014 Academic Editor: Juan F. De Paz Copyright © 2015 Yee Wen Choon et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Microbial strain optimisation for the overproduction of a desired phenotype has been a popular topic in recent years. Gene knockout is a genetic engineering technique that can modify the metabolism of microbial cells to obtain desirable phenotypes. Optimisation algorithms have been developed to identify the effects of gene knockout. However, the complexities of metabolic networks have made the process of identifying the effects of genetic modification on desirable phenotypes challenging. Furthermore, a vast number of reactions in cellular metabolism often lead to a combinatorial problem in obtaining optimal gene knockout.
    [Show full text]
  • The Antidiabetic Drug Lobeglitazone Has the Potential to Inhibit PTP1B T Activity ⁎ Ruth F
    Bioorganic Chemistry 100 (2020) 103927 Contents lists available at ScienceDirect Bioorganic Chemistry journal homepage: www.elsevier.com/locate/bioorg The antidiabetic drug lobeglitazone has the potential to inhibit PTP1B T activity ⁎ Ruth F. Rochaa, Tiago Rodriguesc, Angela C.O. Menegattia,b, , Gonçalo J.L. Bernardesc,d, Hernán Terenzia a Centro de Biologia Molecular Estrutural, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Campus Trindade, 88040-900 Florianópolis, SC, Brazil b Universidade Federal do Piauí, CPCE, 64900-000 Bom Jesus, PI, Brazil c Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028 Lisbon, Portugal d Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, UK ARTICLE INFO ABSTRACT Keywords: Protein tyrosine phosphatase 1B (PTP1B) is considered a potential therapeutic target for the treatment of type 2 Thiazolidinediones diabetes mellitus (T2DM), since this enzyme plays a significant role to down-regulate insulin and leptin sig- Lobeglitazone nalling and its over expression has been implicated in the development of insulin resistance, T2DM and obesity. PPAR-γ Some thiazolidinediones (TZD) derivatives have been reported as promising PTP1B inhibitors with anti hy- PTP1B perglycemic effects. Recently, lobeglitazone, a new TZD, was described as an antidiabetic drug that targetsthe Non-competitive inhibitors PPAR-γ (peroxisome γ proliferator-activated receptor) pathway, but no information on its effects on PTP1B have been reported to date. We investigated the effects of lobeglitazone on PTP1B activity in vitro. Surprisingly, lobeglitazone led to moderate inhibition on PTP1B (IC50 42.8 ± 3.8 µM) activity and to a non-competitive reversible mechanism of action.
    [Show full text]
  • Gene Editing of Microalgae: Scientific Progress and Regulatory
    biology Review Gene Editing of Microalgae: Scientific Progress and Regulatory Challenges in Europe Andrew Spicer 1,* and Attila Molnar 2 ID 1 Algenuity, Eden Laboratory, Bedfordshire MK43 9ND, UK 2 Institute of Molecular Plant Sciences, University of Edinburgh, Edinburgh EH9 3BF, UK; [email protected] * Correspondence: [email protected]; Tel.: +44-1234-765773 Received: 22 December 2017; Accepted: 1 March 2018; Published: 6 March 2018 Abstract: It is abundantly clear that the development of gene editing technologies, represents a potentially powerful force for good with regard to human and animal health and addressing the challenges we continue to face in a growing global population. This now includes the development of approaches to modify microalgal strains for potential improvements in productivity, robustness, harvestability, processability, nutritional composition, and application. The rapid emergence and ongoing developments in this area demand a timely review and revision of the current definitions and regulations around genetically modified organisms (GMOs), particularly within Europe. Current practices within the EU provide exemptions from the GMO directives for organisms, including crop plants and micro-organisms that are produced through chemical or UV/radiation mutagenesis. However, organisms generated through gene editing, including microalgae, where only genetic changes in native genes are made, remain currently under the GMO umbrella; they are, as such, excluded from practical and commercial opportunities in the EU. In this review, we will review the advances that are being made in the area of gene editing in microalgae and the impact of regulation on commercial advances in this area with consideration to the current regulatory framework as it relates to GMOs including GM microalgae in Europe.
    [Show full text]
  • What Are Knockout Mice?
    Lecture 37 Knockout mice Lecture 29 Cloning and Expression vectors Lecture 30 Eukaryotic Protein Expression Systems –I Lecture 31 Eukaryotic Protein Expression Systems –II Lecture 32 Eukaryotic Protein Expression Systems –III Lecture 33 Human Gene Therapy Lecture 34 DNA Vaccines Lecture 35 Transgenic Animals Lecture 36 Transgenic Plants Lecture 37 Knockout Mice What are knockout mice? A knockout mouse is a mouse in which a specific gene has been inactivated or “knocked out” by replacing it or disrupting it with an artificial piece of DNA. The loss of gene activity often causes changes in a mouse's phenotype and thus provides valuable information on the function of the gene. Researchers who developed the technology for the creation of knockout mice won Nobel Prize in the year 2007 The Nobel Prize in Physiology or Medicine 2007 was awarded jointly to Mario R. Capecchi, Sir Martin J. Evans and Oliver Smithies "for their discoveries of principles for introducing specific gene modifications in mice by the use of embryonic stem cells". Mario R. Capecchi Sir Martin J. Evans Oliver Smithies The ability to delete or mutate any gene of interest in mice has transformed the landscape of mammalian biology research. Cultivation of embryonic stem (ES) cells – Martin Evans • Gene targeting – Oliver Smithies • Gene knockout – Mario Capecchi Gene correction by Oliver Smithies Targeted correction of a mutant HPRT gene in mouse ES cells. Nature 330:576-8, 1987 This modification of a chosen gene in pluripotent ES cells demonstrates the feasibility of this route to manipulating mammalian genomes in predetermined ways. -------------------------------------------------------------------------------------- Nature. 1985 Sep 19-25;317(6034):230-4.
    [Show full text]
  • Step-By-Step Knockout (Dsdna) Protocol.Pdf
    Court Lab Protocol 3/21/11 Recombineering: Using Drug Cassettes to Knock out Genes in vivo James A. Sawitzke1, Lynn C. Thomason2, Mikhail Bubunenko1,2, Xintian Li1, Nina Costantino1, and Donald L. Court1 1Molecular Control and Genetics Section, Gene Regulation and Chromosome Biology Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702 2Gene Regulation and Chromosome Biology Laboratory, Basic Science Program, SAIC-Frederick, Inc., National Cancer Institute at Frederick, Frederick, MD 21702 Purpose A “gene knockout” or “knockout” is a mutation that inactivates a gene function. These mutations are very useful for classical genetic studies as well as for modern techniques including functional genomics. In the past, knockouts of bacterial genes were often made by transposon mutagenesis. In this case, laborious screens are required to find a knockout in the gene of interest. Knockouts of other organisms have traditionally been made by first using in vitro genetic engineering to modify genes contained on plasmids or Bacterial Artificial Chromosomes (BACs) and later moving these modified constructs to the organism of interest by cell culture techniques. Other methods utilizing a combination of genetic engineering and in vivo homologous recombination were inefficient at best. Recombineering provides a new way to generate knockout mutations directly on the bacterial chromosome or to modify any plasmid or BAC in vivo as a prelude to making knockouts in other organisms. The constructs are designed to the base pair and are not dependent on suitable restriction sites. A drug cassette can be placed anywhere within a gene or the open reading of the gene can be replaced with the drug cassette.
    [Show full text]
  • Generation of Mouse Conditional Knockout Alleles in One Step Using the I-GONAD Method
    Downloaded from genome.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Method Generation of mouse conditional knockout alleles in one step using the i-GONAD method Renjie Shang,1,2 Haifeng Zhang,1 and Pengpeng Bi1,2 1Center for Molecular Medicine, University of Georgia, Athens, Georgia 30602, USA; 2Department of Genetics, University of Georgia, Athens, Georgia 30602, USA The Cre/loxP system is a powerful tool for gene function study in vivo. Regulated expression of Cre recombinase mediates precise deletion of genetic elements in a spatially– and temporally–controlled manner. Despite the robustness of this system, it requires a great amount of effort to create a conditional knockout model for each individual gene of interest where two loxP sites must be simultaneously inserted in cis. The current undertaking involves labor-intensive embryonic stem (ES) cell– based gene targeting and tedious micromanipulations of mouse embryos. The complexity of this workflow poses formida- ble technical challenges, thus limiting wider applications of conditional genetics. Here, we report an alternative approach to generate mouse loxP alleles by integrating a unique design of CRISPR donor with the new oviduct electroporation technique i-GONAD. Showing the potential and simplicity of this method, we created floxed alleles for five genes in one attempt with relatively low costs and a minimal equipment setup. In addition to the conditional alleles, constitutive knockout alleles were also obtained as byproducts of these experiments. Therefore, the wider applications of i-GONAD may promote gene func- tion studies using novel murine models. [Supplemental material is available for this article.] Our understanding of the genetic mechanisms of human diseases strains are readily available, generation of the loxP-flanked (floxed) has been largely expanded by loss-of-function studies using engi- alleles is challenging and labor-intensive due to the lack of an effi- neered mouse models.
    [Show full text]
  • Prospects of Gene Knockouts in the Functional Study of MAMP-Triggered Immunity: a Review
    International Journal of Molecular Sciences Review Prospects of Gene Knockouts in the Functional Study of MAMP-Triggered Immunity: A Review Benedict C. Offor , Ian A. Dubery and Lizelle A. Piater * Department of Biochemistry, University of Johannesburg, Auckland Park 2006, South Africa; benedictoff[email protected] (B.C.O.); [email protected] (I.A.D.) * Correspondence: [email protected]; Tel.: +27-11-559-2403 Received: 5 March 2020; Accepted: 1 April 2020; Published: 6 April 2020 Abstract: Plants depend on both preformed and inducible defence responses to defend themselves against biotic stresses stemming from pathogen attacks. In this regard, plants perceive pathogenic threats from the environment through pattern recognition receptors (PRRs) that recognise microbe-associated molecular patterns (MAMPs), and so induce plant defence responses against invading pathogens. Close to thirty PRR proteins have been identified in plants, however, the molecular mechanisms underlying MAMP perception by these receptors/receptor complexes are not fully understood. As such, knockout (KO) of genes that code for PRRs and co-receptors/defence-associated proteins is a valuable tool to study plant immunity. The loss of gene activity often causes changes in the phenotype of the model plant, allowing in vivo studies of gene function and associated biological mechanisms. Here, we review the functions of selected PRRs, brassinosteroid insensitive 1 (BRI1) associated receptor kinase 1 (BAK1) and other associated defence proteins that have been identified in plants, and also outline KO lines generated by T-DNA insertional mutagenesis as well as the effect on MAMP perception—and triggered immunity (MTI). In addition, we further review the role of membrane raft domains in flg22-induced MTI in Arabidopsis, due to the vital role in the activation of several proteins that are part of the membrane raft domain theory in this regard.
    [Show full text]
  • AVANDIA (Rosiglitazone Maleate Tablets), for Oral Use Ischemic Cardiovascular (CV) Events Relative to Placebo, Not Confirmed in Initial U.S
    HIGHLIGHTS OF PRESCRIBING INFORMATION ----------------------- WARNINGS AND PRECAUTIONS ----------------------- These highlights do not include all the information needed to use • Fluid retention, which may exacerbate or lead to heart failure, may occur. AVANDIA safely and effectively. See full prescribing information for Combination use with insulin and use in congestive heart failure NYHA AVANDIA. Class I and II may increase risk of other cardiovascular effects. (5.1) • Meta-analysis of 52 mostly short-term trials suggested a potential risk of AVANDIA (rosiglitazone maleate tablets), for oral use ischemic cardiovascular (CV) events relative to placebo, not confirmed in Initial U.S. Approval: 1999 a long-term CV outcome trial versus metformin or sulfonylurea. (5.2) • Dose-related edema (5.3) and weight gain (5.4) may occur. WARNING: CONGESTIVE HEART FAILURE • Measure liver enzymes prior to initiation and periodically thereafter. Do See full prescribing information for complete boxed warning. not initiate therapy in patients with increased baseline liver enzyme levels ● Thiazolidinediones, including rosiglitazone, cause or exacerbate (ALT >2.5X upper limit of normal). Discontinue therapy if ALT levels congestive heart failure in some patients (5.1). After initiation of remain >3X the upper limit of normal or if jaundice is observed. (5.5) AVANDIA, and after dose increases, observe patients carefully for signs • Macular edema has been reported. (5.6) and symptoms of heart failure (including excessive, rapid weight gain; • Increased incidence of bone fracture was observed in long-term trials. dyspnea; and/or edema). If these signs and symptoms develop, the heart (5.7) failure should be managed according to current standards of care.
    [Show full text]
  • The Effect of Rosiglitazone on Overweight Subjects with Type 1 Diabetes
    Clinical Care/Education/Nutrition ORIGINAL ARTICLE The Effect of Rosiglitazone on Overweight Subjects With Type 1 Diabetes SUZANNE M. STROWIG, MSN, RN the potentially serious consequences of PHILIP RASKIN, MD excessive weight gain and insulin- induced hypoglycemia, investigators con- tinue to search for treatments that address both the treatment of insulin deficiency as well as other metabolic abnormalities that OBJECTIVE — To evaluate the safety and effectiveness of rosiglitazone in the treatment of are associated with diabetes (5). overweight subjects with type 1 diabetes. Insulin resistance, a metabolic abnor- mality common in type 2 diabetes, ap- RESEARCH DESIGN AND METHODS — A total of 50 adult type 1 diabetic subjects 2 pears to be present in individuals with with a baseline BMI Ն27 kg/m were randomly assigned in a double-blind fashion to take insulin and placebo (n ϭ 25) or insulin and rosiglitazone 4 mg twice daily (n ϭ 25) for a period of 8 type 1 diabetes, as well. Although insulin months. Insulin regimen and dosage were modified in all subjects to achieve near-normal resistance in type 2 diabetes is generally glycemic control. associated with obesity, hypertension, dyslipidemia, and other metabolic disor- RESULTS — Both groups experienced a significant reduction in HbA1c (A1C) level (rosigli- ders, studies have shown that overweight tazone: 7.9 Ϯ 1.3 to 6.9 Ϯ 0.7%, P Ͻ 0.0001; placebo: 7.7 Ϯ 0.8 to 7.0 Ϯ 0.9%, P ϭ 0.002) and as well as normal-weight adults with type a significant increase in weight (rosiglitazone: 97.2 Ϯ 11.8 to 100.6 Ϯ 16.0 kg, P ϭ 0.008; 1 diabetes can have peripheral and he- Ϯ Ϯ ϭ ϭ placebo: 96.4 12.2 to 99.1 15.0, P 0.016).
    [Show full text]
  • AVANDIA® (Rosiglitazone Maleate) Tablets
    PRESCRIBING INFORMATION AVANDIA® (rosiglitazone maleate) Tablets WARNING: CONGESTIVE HEART FAILURE ● Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive heart failure in some patients (see WARNINGS). After initiation of AVANDIA, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of AVANDIA must be considered. ● AVANDIA is not recommended in patients with symptomatic heart failure. Initiation of AVANDIA in patients with established NYHA Class III or IV heart failure is contraindicated. (See CONTRAINDICATIONS and WARNINGS.) DESCRIPTION AVANDIA (rosiglitazone maleate) is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity. AVANDIA is used in the management of type 2 diabetes mellitus (also known as non-insulin-dependent diabetes mellitus [NIDDM] or adult-onset diabetes). AVANDIA improves glycemic control while reducing circulating insulin levels. Pharmacological studies in animal models indicate that rosiglitazone improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Rosiglitazone maleate is not chemically or functionally related to the sulfonylureas, the biguanides, or the alpha-glucosidase inhibitors. Chemically, rosiglitazone maleate is (±)-5-[[4-[2-(methyl-2- pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, (Z)-2-butenedioate (1:1) with a molecular weight of 473.52 (357.44 free base). The molecule has a single chiral center and is present as a racemate. Due to rapid interconversion, the enantiomers are functionally indistinguishable. The structural formula of rosiglitazone maleate is: The molecular formula is C18H19N3O3S•C4H4O4.
    [Show full text]
  • Muraglitazar Bristol-Myers Squibb/Merck Daniella Barlocco
    Muraglitazar Bristol-Myers Squibb/Merck Daniella Barlocco Address Originator Bristol-Myers Squibb Co University of Milan . Istituto di Chimica Farmaceutica e Tossicologica Viale Abruzzi 42 Licensee Merck & Co Inc 20131 Milano . Italy Status Pre-registration Email: [email protected] . Indications Metabolic disorder, Non-insulin-dependent Current Opinion in Investigational Drugs 2005 6(4): diabetes © The Thomson Corporation ISSN 1472-4472 . Actions Antihyperlipidemic agent, Hypoglycemic agent, Bristol-Myers Squibb and Merck & Co are co-developing Insulin sensitizer, PPARα agonist, PPARγ agonist muraglitazar, a dual peroxisome proliferator-activated receptor-α/γ . agonist, for the potential treatment of type 2 diabetes and other Synonym BMS-298585 metabolic disorders. In November 2004, approval was anticipated as early as mid-2005. Registry No: 331741-94-7 Introduction [579218], [579221], [579457], [579459]. PPARγ is expressed in Type 2 diabetes is a complex metabolic disorder that is adipose tissue, lower intestine and cells involved in characterized by hyperglycemia, insulin resistance and immunity. Activation of PPARγ regulates glucose and lipid defects in insulin secretion. The disease is associated with homeostasis, and triggers insulin sensitization [579216], older age, obesity, a family history of diabetes and physical [579218], [579458], [579461]. PPARδ is expressed inactivity. The prevalence of type 2 diabetes is increasing ubiquitously and has been found to be effective in rapidly, and the World Health Organization warns that, controlling dyslipidemia and cardiovascular diseases unless appropriate action is taken, the number of sufferers [579216]. PPARα agonists are used as potent hypolipidemic will double to over 350 million individuals by the year compounds, increasing plasma high-density lipoprotein 2030. Worryingly, it is estimated that only half of sufferers (HDL)-cholesterol and reducing free fatty acids, are diagnosed with the condition [www.who.int].
    [Show full text]
  • CRISPR-Based Editing Techniques for Genetic Manipulation of Primary T Cells
    Review CRISPR-Based Editing Techniques for Genetic Manipulation of Primary T Cells Mateusz Kotowski and Sumana Sharma * MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK; [email protected] * Correspondence: [email protected] Received: 15 October 2020; Accepted: 14 November 2020; Published: 18 November 2020 Abstract: While clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing techniques have been widely adapted for use in immortalised immune cells, efficient manipulation of primary T cells has proved to be more challenging. Nonetheless, the rapid expansion of the CRISPR toolbox accompanied by the development of techniques for delivery of CRISPR components into primary T cells now affords the possibility to genetically manipulate primary T cells both with precision and at scale. Here, we review the key features of the techniques for primary T cell editing and discuss how the new generation of CRISPR-based tools may advance genetic engineering of these immune cells. This improved ability to genetically manipulate primary T cells will further enhance our fundamental understanding of cellular signalling and transcriptional networks in T cells and more importantly has the potential to revolutionise T cell-based therapies. Keywords: primary T cells; CRISPR/Cas9; genome-editing; CAR-T cells 1. Introduction In recent years, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR- associated protein 9 (Cas9)-based techniques have transformed our ability to genetically manipulate mammalian genomes. Among the many fields within biomedical research to benefit from the ease of genetic manipulation using the CRISPR/Cas9 system is the study of the immune system and especially T cells.
    [Show full text]